This paper reviews the latest research in the
field of the neurobiology of schizophrenia. Particular emphasis
is placed on the microanatomical studies showing loss of dendritic
spines and loss of neuropil and the studies implicating abnormal
redox functions at the glutamate synapse. Particular attention
is paid to ketamine and whether it acts as an indirect agonist
or an antagonist at the NMDA receptor. There is evidence that
oxidative stress plays a role in the disease. The role of catecholamine
o-quinones derived from dopamine, noradrenaline and adrenaline
in the brain is reviewed. One of these (adrenochrome) was demonstrated
forty years ago to be a psychotomimetic agent. Thus these o-quinones
may play a role in the illness.

Neuroanatomical studies

In recent years research into the biological basis
of schizophrenia has focused on anatomical damage and the biochemical
mechanisms that may underlie this. At the macroanatomical level
there is general agreement that many cases, particularly of type
II schizophrenia show enlarged ventricles and cortical atrophy,
especially in the temporal lobes and prefrontal cortex (Nopoulos
et al, 1995; Lim et al, 1996; Marsh et al, 1997; Ziparsky et al,
1997; Sullivan et al, 1998). Dissenting opinions have been voiced
by Dwork (1997: except for enlarged lateral ventricles)
and Heckers (1997: no strong clinicopathological correlations).
This atrophy appears to be progressive over time in certain cases
(DeLisi et al, 1997; Nair et al, 1997; Rapoport, 1997; Gur et
al, 1998). Similar changes have been found in the normal siblings
of schizophrenic cases (Seidman et al, 1997). A loss of cells
in the dorsomedial nucleus of the thalamus has been reported by
some (Pakkenberg, 1990; Jones, 1997; Lewis, 1997) but denied by
others (Lesch and Bogerts, ; Jernigan et al, 1991: and see Weinberger,
1997). Portas et al (1998) found reduced connectivity between
the thalamus and the cortex.

Neurochemical studies

The glutamate synapse

Earlier work in this field concentrated upon looking
for abnormalities in the number or function of receptors for biogenic
amines. Now the focus of studies has shifted towards the glutamate
synapse and towards 'deeper' aspects of neuronal function such
as post-synaptic cascades, the molecular mechanisms of synaptic
formation, cohesion and elimination, transcription mechanisms,
redox systems and others. Clearly the place to start looking today,
in view of the microanatomical evidence listed earlier, is at
the mechanisms that are responsible for synaptic growth and deletion,
particularly on dendritic spines. It so happens that this system
closely involves the glutamate synapse. Interest in the glutamate
system arose because it was noted that drugs that act on the NMDA
glutamate receptor, such as ketamine and PCP, at low dose produce
a model schizophrenic-like psychosis. It would therefore be appropriate
to start with an account of the relevant parts of this synapse.

Activation of the NMDA receptor opens a calcium channel
which starts a number of post-synaptic cascades. Ca + ions
activate a number of neurodestructive proteases and nucleases.
They also activate the enzyme phospholipase A2 which converts
membrane phospholipids into arachidonic acid (AA). AA in turn
activates the enzyme prostaglandin H synthase, the rate-limiting
step in prostaglandin synthesis. This activation releases a large
amount of reactive oxygen species (ROS) including the superoxide
anion and the freely diffusable molecule hydrogen peroxide. Ca++
also activates the enzyme nitric oxide synthase, which process
also releases large quantities of ROS and freely diffusible nitric
oxide, which, in its dominant nitric oxide radical form, is a
pro-oxidant. The free diffusion of H2O2
and NO back into the glutamate synapse would have pro-oxidant
neurotoxic effects if it were not balanced by antioxidant defenses.
The principle antioxidant defenses at the glutamate synapse are
(i) ascorbate which is released into the synapse by the Na+/K+
ATPase-dependent glutamate transporter in exchange for glutamate
during the reuptake process which terminates glutamate action,
(ii) carnosine which is released together with glutamate from
the synaptic vesicle and (iii) probably glutathione. There is
also a redox sensitive site on the NMDA receptor protein which
upon oxidation down regulates the NMDAr thus serving as protective
negative feedback to shut off the source of ROS and RNS. Thus
an important factor in the plasticity of the synapse (i.e. whether
it grows or is deleted) may be the redox balance inside the synapse
between neurotoxic pro-oxidants and neuroprotective antioxidants.

Another important component of the redox balance
is likely to be dopamine released from adjacent dopamine boutons-en-passage
and diffusing into the glutamate synapse (Smythies, 1997a,b).
Dopamine is a potent antioxidant as are all catecholamines. The
antioxidant mechanism entails redox cycling between dopamine and
dopamine quinone driven by free radical scavenging in one direction
and reduction of the dopamine quinone by ambient antioxidants,
such as ascorbate and glutathione, in the other direction. This
may constitute a basic mechanism underlying learning and neural
computation since dopamine release is contingent upon positive
reinforcement being received by the organism. Thus dopamine release
would tilt the redox balance towards the neuroprotective reductive
side and would result in synaptic growth. Lack of dopamine would
have the opposite effect. Another mechanism whereby dopamine can
alter the redox balance of neurons is the fact that D2 receptor
activation leads to increased synthesis of antioxidant proteins
-probably superoxide dismutase (Sawada et al, 1998). It is of
interest that one effect of nerve growth factor (also involved
in synaptic plasticity) is to increase the antioxidant defenses
of the neuron by three mechanisms (i) inducing the activity of
the antioxidant enzymes glutathione peroxidase and catalase (Goss
et al, 1997; Sampath and Perez-Polo, 1997), (ii) lowering ROS
production by inhibiting mitochondrial respiration and arachidonic
acid metabolism -both potent sources of ROS production (Dugan
et al. 1997), and (iii) by inhibiting ROS production by a carpase-linked
mechanism (Schulz et al, 1997).

However, the entry of dopamine into the glutamate
synapse would carry a risk because, in conditions of reduced antioxidant
cover, dopamine can be easily oxidized further than dopamine quinone,
either spontaneously or by peroxynitrite (produced by the interaction
of NO and the superoxide anion) to form cyclized dopamine o-quinones
including the highly toxic free radical o-semiquinone (Smythies,
1997a,b; Smythies and Galzigna, 1998). This also applies to other
catecholamines in the brain, namely noradrenaline and possibly
adrenaline. The noradrenergic neurons in the locus coeruleus and
the C1-C3 neurons in the medulla both contain neuromelanin (Bogert,
1981; Saper and Petito, 1982). However, Gai et al (1993) claim
that it is mainly the non-adrenergic pigmented neurons (that presumably
contain some other catecholamine) in the C1-C3 group that contain
the neuromelanin. But this work was carried out in patients with
advanced Parkinsonís disease and needs to be repeated with
normal brains. So we can infer that the noradrenergic and dopamine
neurons in the brain contain o-quinones, which are obligatory
metabolic precursors of neuromelanin. But further work needs to
be done on the adrenergic system before we can say that adrenochrome
occurs in brain. It is of course possible that adrenaline may
be oxidized in brain tissue to form adrenochrome but for some
reason this does not lead to neuromelanin formation. One explanation
for this may be that a major metabolite of adrenochrome is adrenolutin
in which the 3 -OH group is replaced by =O. This cannot form dihydroxyindole
which is the necessary precursor for neuromelanin formation. Adrenolutin
(but not adrenochrome) has been reported to be present in normal
plasma (Dhalla et al. 1989) but no one as yet has looked for it
in the brain.

Adrenochrome has been shown to be a psychotomimetic
agent (Hoffer et al, 1954, Schwartz et al, 1956; Taubman and Jantz,
1957; Grof, 1963). No such tests have yet been carried out on
noradrenochrome or dopaminochrome. The C1-C3 group are thought
to be concerned in stress responses and project to the medial
thalamus (Phillipson & Bohn. 1994; Otake et al. 1995; Rico
& Cavada. 1998) and substantia nigra (Nagatsu et al. 1998).
Furthermore phenylethylanolamine N-methyl transferase activity
in human brain was found to be high in the RF, hypothalamus and
locus coeruleus, and intermediate in the SN, amygdala, septum,
periacqueductal grey, and central thalamus (the medial thalamus
was not looked at) in a report by Lew et al. 1977). Mefford et
al (1978) report that adrenaline levels are high in the medial
thalamus as well as the hypothalamus and septum. All this suggests
that the medullary adrenergic system may not only be concerned
with lower visceral functions in the brain as was once thought,
but may powerfully modulate key limbic higher functions in particular
those related to stress.

Direct evidence of catecholamine o-quinone production
in brain is furnished by the detection of a metabolite of dopamine
o-quinone -5-cysteinyl dopamine -by Carlsson et al, (1994). Levels
of this compound are raised in the brain in schizophrenia indicating
increased auto-oxidation of dopamine by the quinone pathway.

Intraventricular infusions of dopamine in humans
every 3 weeks led to the development of paranoid delusions (but
no hallucinations or thought disorder) that lasted 2 weeks after
each infusion (Kulkarni et al., 1992). This may have been due
to over-stimulation of dopamine receptors. It may also have been
due to the neurotoxic effects of quinone metabolic products of
the dopamine.

Direct studies of the glutamate synapse

(i) mRNAs for AMPA receptors subunits R1 and R2 have
been reported by one group to be reduced in the hippocampus (Eastwood
et al, 1997a), medial temporal lobe (Eastwood et al, 1997b) and
in the subiculum and parahippocampal gyrus (Kerwin and Harrison,
1995). The same group also report altered AMPA receptor desensitization
kinetics (changes in flip-flop ratios) in remaining R2 subunits
(Eastwood et al, 1997a). They conclude that subtle, progressive
excitotoxic damage may be involved.í (Eastwood et al, 1997b).

(ii) The same group report an increase in mRNAs for
NR1 and NR2A (but not NR2B) subunits of the NMDA receptor in the
hippocampus (Beckwith et al. 1995b). Another group (Humphries
et al, 1995; Humphries et al, 1996; Hirsch et al, 1997) report
a decrease in mRNAs for the NMDA R1 subunit in the superior temporal
cortex in cognitively impaired but not unimpaired schizophrenics.
Goff and Wine (1997) found that NMDArs have raised levels of 2D
subunits, which would result in higher sensitivity to glutamate.
They also found more unedited AMPArs, which would increase Ca++
inflow. This data would support increased excitotoxic damage in
the disease.

In contrast, Meador-Woodruff et al (1997b) failed
to find any abnormality in mRNAs for ionotrophic glutamate receptors
in the prefrontal cortex, hippocampus, septum and striatum in
schizophrenic brains. A loss of glutamate terminals in the hippocampus
and polar temporal cortex (Deakin and Simpson, 1997) and of non-NMDArs
in the hippocampus (Beckwith et al, 1995a) have also been reported.

Indirect studies of the glutamate synapse

Ketamine

This anesthetic drug is usually described as an antagonist
at the glutamate receptor. Therefore, since it produces psychotic
reactions at sub-anesthetic doses, schizophrenia has been attributed
to underactivity at glutamate synapses. However, glutamate excitotoxicity,
which has also been linked to schizophrenia, involves overactivity
at glutamate synapses. This led Olner and Farber (1995) to suggest
that an early over-activity of glutamate synapses might destroy
GABAergic neurons, or NMDArs on their surface, and so lead to
disinhibition of glutamate systems downstream. This overlooks
the fact that GABArs are continually being synthesized and so
a local destruction would have to be continually maintained in
order to result in a chronic disease.

However, there is a simpler explanation. Ketamine
at subanesthetic doses leads to increased glutamate release and
subsequent increased stimulation of AMPA receptors (which open
channels that allow ingress of Ca++ as well as Na+)
as well possibly of NMDArs not blocked by ketamine at this lower
dose -in other words it would act as an indirect AMPA/NMDA agonist
at this low dose (Moghaddam et al, 1997; Moghaddam, 1997). Hoffman
and McGlashan (1997) also point out that that the dose used in
animals (0.5-50 mg/kg) to demonstrate NMDAr antagonism is much
larger than the psychotomimetic dose used in humans (0.05-0.1
mg/kg). They suggest that the lesion in schizophrenia may be reduced
cortical connectivity rather than receptor dysfunction.

Low doses of ketamine increase 2-DG uptake in the
limbic cortex and subcortex, whereas high doses reduce 2-DG uptake
globally (Duncan et al, 1998). Low doses of ketamine also promote
FOS-L1 induction in limbic cortex (but not in limbic subcortex),
whereas high doses lead to a robust increase of FOS-L1 induction
(Duncan et al, 1998). These workers suggest that ketamine may
produce its psychotomimetic effect by two mechanisms (i) by the
one suggested by Olney and Farber (1995) and (ii) by increasing
glutamate release. Anesthetic doses of ketamine inhibit glutamate
release. The hypothesis that the psychotomimetic effect of ketamine
and PCP is due primarily to increased, not decreased, glutamatergic
activity is supported by the observation that acute administration
of PCP (i) increases the expression of COX-2 mRNA in rat retrosplenial
cortex which indicates activation of the post-NMDAr cascade (COX-2
is a part of the PGH synthase complex) (Hashimoto et al, 1997).
and (ii) increases the production of mRNA for glutamate dehydrogenase
(Shimizu et al, 1997) which these authors suggest is compensatory
for increased glutamate release. In monkeys PCP given acutely
activates the mesoprefrontal dopamine system (Jentsch et al, 1998)
due, these authors suggest, to a decrease in the inhibition of
the dopamine system by glutamate. In contrast chronic administration
of PCP inhibits DA turnover. Which of these effects is related
to the psychotomimetic effects of PCP is unclear.

There is also data from research into the mode of
action of antipsychotic drugs on this system to support the hypothesis
of an initial over-activity of the glutamate system which could
lead to subtle, progressive excitotoxic damage which
would result to later underactivity of this damaged system. However,
this damage is to replaceable spines and neuropil not to irreplaceable
neurons. Lidsky et al (1997) state that low doses of antipsychotic
drugs enhance NMDA activity possibly (a) because they block dopamine
presynaptic D2 receptors, leading to an increase in extracellular
dopamine, which in turn would block glutamate reuptake, resulting
in increased intrasynaptic glutamate levels and (b) because dopamine
acting post-synaptically at D1 receptors enhances glutamate activated
G-protein linked adenylate cyclase activation. This group claims
that antipsychotics are NMDA antagonists only at high doses (Lidsky
et al, 1997). Bannerjee et al. (1996) state that haloperidol and
clozepine are potent augmentors (rather than antagonists) at the
NMDAr. In contrast Ilyin et al. (1996) state that haloperidol
is an NMDAr blocker (by a direct allosteric effect on the receptor
protein) and only at very low doses may potentiate NMDAr activity.
Coughenour et al (1997) also support the claim that haloperidol
is a non-competitive allosteric antagonist at the NMDAr. Clearly,
if antipsychotic agents are NMDA receptor blockers (at the relevant
dose), then ketamine is hardly likely to act as an NMDAr antagonist
in the production of its psychotomimetic effect..

A complication is introduced by Halberstadt (1995)
who claims that haloperidol does not bind to NMDArs but to sigma
receptors. Sharp (1997) states that PCP binds to NMDArs (which
does not lead to an induction of c-fos production) and to sigma
receptors (which results in abundant c-fos production in the cingulate,
parietal, and piriform cortex, midline thalamus, hypothalamus,
but not in the hippocampus). Thus the binding to sigma receptors
might appear to be more important. Sharp (1997) further states
that there are no known endogenous ligands for the sigma receptor
and its normal physiological function is also unknown. One additional
interesting datum is that sigma receptor antagonists (such as
rimcazole) block PCP-induced stereotyped behavior and inhibit
PCP-induced c-fos production.

Further support for the hypothesis that psychotic
reactions are associated, at least at some stage, by over-activity
rather than under-activity at NMDA receptors is the reported successful
use of the NMDAr antagonist amantadine in the treatment of catatonic
schizophrenia (Northoff et al, 1997). Kornhuber et al (1997 and
Kroemer et al (1998) have stressed the therapeutic promise of
low-affinity uncompetitive NMDA antagonists like amantadine and
memantine in protection against glutamate toxicity. Ketamine increases
cortical blood flow in the anterior cingulate and right inferior
frontal lobe in both schizophrenics and normals and decreases
it in the left middle temporal cortex only in schizophrenics (Lahti
et al, 1997).

The mixed apoptotic/necrotic effect of chronic administration
of PCP is prevented by pretreatment with clozepine (Johnson et
al, 1998). The pattern of degeneration produced by PCP follows
the distribution of mRNAs for the NR1 subunit of the NMDAr and
of dopamine. These authors suggest that the toxic effects of PCP
given chronically involves NMDAr overactivity.

To conclude this section, the evidence seems to support
the hypothesis that schizophrenia, and the effects of psychotomimetic
doses of ketamine, is associated with a shift in the balance of
glutamate receptor function towards chronic local excitotoxic
over-stimulation of the post-synaptic cascade, and/or the production
of excessive amounts of ROS/neurotoxins by this cascade, leading
to dynamic damage to the post-synaptic spines and their replacements
and so a functional overall underactivity of the excitatory network
results (loss of dendritic spines and functional synapses) (Benes,
1995). Based on neural net computer modeling Hoffman and McGlashan
(1993) have pointed out that excessive pruning of dendritic spines
and reduced cortical connectivity would lead to the formation
of parasitic foci in the non-linear dynamical attractor
networks of the brain. This leads to bizarre outputs, functionally
autonomous sub-populations, and the locking of some modules into
cognitive outputs independent of the input, all of which in a
real brain could underlie the symptoms seen in schizophrenia.
EEG support for this hypothesis has been provided by Lutzenberger
et al (1995).

The redox balance in schizophrenia

Studies of antioxidant systems in schizophrenia has
produced the usual medley of conflicting results. In red blood
cells SOD has been reported as lowered (Mahadik and Mukherjee,
1996) and raised (Abdalla et al, 1986; Reddy et al, 1991); GSHpx
as lowered (Abdalla et al, 1986) and as normal (Mahadik and Mukherjee,
1996; Reddy et al, 1991); CAT as normal (Mahadik and Mukherjee,
1996) and as lowered (Reddy and Yao, 1996). Buckman et al (1990)
report a strong negative correlation between brain atrophy and
platelet GSHpx levels. They suggest the hypothesis that low GSHpx
levels may constitute a vulnerability factor to oxidative stress.
CAT activity in brain is low, and is located mainly in astrocytes.
Therefore GSHpx (located mainly in neurons) is important. In the
brain Loven et al (1996) found that Mn SOD activity was markedly
raised (which would lead to excess production of hydrogen peroxide)
in the temporal cortex and frontal cortex of a group of psychotic
patients on neuroleptics, but there was no change in Cu/Zn SOD
activity. Levels of the blood antioxidants albumin, uric acid
and bilirubin are reduced (Yao et al, 1998a,b) and total antioxidant
capacity is low (Yao et al, 1998c). These changes are correlated
with the clinical severity of the disease. There is evidence that
TBARS, a marker of lipid oxidation, is raised in schizophrenia
(Mahadik et al, 1998) and that superoxide production by neutrophils
is raised (Melamed et al, 1998) both indicating the presence of
increased oxidative stress.

Synaptic associated proteins

The suggestion that schizophrenia may be associated
with synaptic malfunction or damage has led to studies of synaptic-associated
proteins in post-mortem brains. Reduced levels of synaptophysin
have been reported in the prefrontal cortex (Karson et al, 1997;
Glantz and Lewis, 1997), and in association cortex (Perrone-Bizzozero
et al, 1996) but also denied Browning et al (1993) who reported
instead reduced levels of synapsin. Levels of mRNAs coding for
synapsin 1A and 1B and synaptophysin have been reported to be
raised in the left superior and middle temporal cortex Tcherepanov
and Sokolov, 1997). Levels of the synaptic vesicle protein rab3a
have been reported to be reduced in the left but not the right
thalamus (Blennow et al. 1996) associated with decreased synaptic
density. Levels of the neural cell adhesion molecule N-CAM 105-115-kDA
are raised in the hippocampus and prefrontal cortex (Vawter et
al, 1998). In a study of monozygotic twins discordant for schizophrenia
(Poltorak et al, 1997), the schizophrenic twin showed higher CSF
levels of N-CAM and lower levels of L1 antigen, with no change
in contractin levels. Another study (Honer et al, 1997) N-CAM
and syntaxin levels were both reported to be raised. As the latter
is found only in conjunction with excitatory terminals, the authors
suggest that this finding indicates increased glutamate activity
in the cingulate cortex. Cotter et al (1997) report an increase
in the expression of non-phosphorylated MAPs in the subiculum
suggesting an abnormal assembly of cytoskeletal proteins. GAP-43
levels have been reported to be raised in association cortex (Perrone-Bizzozero
et al, 1996) but their mRNAs reduced in selected areas (Eastwood
and Harrison, 1998). This protein is involved in the initial establishment
and later reorganization of synaptic connections. Similar complexities
are revealed by Thompson et al (1998) who measured levels of the
synaptosomal associated protein SNAP-25 and found levels to be
decreased in the inferior temporal cortex and prefrontal cortex
(area 10), increased in the prefrontal cortex (area 9) and normal
in area 17.

In view of these conflicting results and the early
state of this work it would be premature to try to draw any conclusions.
However it is clearly a field of great promise.

NAA/creatinine ratios

NAA/creatine and NAA/choline ratios as obtained by
proton magnetic resonance spectroscopy gives a measure of neuronal
damage in the living human. These ratios have been reported to
be reduced in various brain areas (Bertolino et al, 1996, 1998;
Yurgelun-Todd et al, 1996). However, Lim et al (1998) found that
in cortical grey matter the NAA signal was normal but the grey
matter volume was reduced, whereas in cortical white matter it
was the other way round. They suggested that their results indicated
abnormal axonal connections.

Receptors

Dopamine

The literature on alleged abnormalities of DA receptors
in schizophrenia is vast and full of contradictions. Halberstadt
(1995) says that there is no reliable evidence for the dopamine
hypothesis. It seems that previously claimed increases in striatal
D1 and D2 receptors were probably due to neuroleptic medication
(Knable et al, 1994; Reynolds 1995; Hietala and Syvälahti,
1996), and that D3 and/or D4 receptors may be normal (Lahti et
al, 1996; Reynolds and Mason 1994; Helmeste et al, 1996). Previous
claims that D4 receptors are increased (Seeman et al, 1993; Marzella
et al, 1997) have been criticized on methodological grounds (Meador-Woodruff
et al, 1997a) One recent study (Joyce et al 1997) reported that
D3 receptors in schizophrenic subjects drug free for one year
were increased in the target area of the mesolimbic tract together
with an altered laminar distribution of D2 receptors in the temporal
lobe. One study actually reported a reduction of D1 receptors
in the prefrontal cortex (but not the striatum) related to the
severity of negative symptoms (Okubo et al, 1997). Meador-Woodfruff
et al (1997a) found a marked reduction of mRNAs for D3 and D4
receptors in orbitofrontal cortex. Opeskin et al, 1996) found
that D2 second messenger systems (PKC and adenylate cyclase) were
not altered in the striatum in schizophrenia. Sigma receptors
however may be reduced (Helmeste et al, 1996).

Since receptor molecules are continually being replaced,
any chronic abnormality in receptor numbers or function is likely
to reflect a disorder in the dynamic mechanism of receptor production
and matching to loading, including protein synthesis, nuclear
transcription, second messengers, etc. Furthermore, even if receptor
numbers are found to be increased, or decreased, this may well
represent secondary changes to a primary disturbance in some more
basic mechanism.

The transmethylation and one-carbon cycle hypotheses
of schizophrenia and affective disorders have recently been reviewed
elsewhere (Smythies et al, 1997). The key finding is that enzymes
of the one-carbon cycle (MAT and SHMT) are impaired in schizophrenia
that would be expected to lead to defective transmethylation mechanisms.
It is noteworthy that O-methylation of catecholamine o-hydroquinones
is a mechanism that prevents the formation of the toxic free radical
o-semiquinone.

Conclusion

This review suggests that the most promising area
for future research in schizophrenia are the mechanisms by which
abnormal function at the glutamate synapse leads to excessive
spine pruning, and loss of neuropil and inter-neural connectivity.
These mechanisms may include oxidative stress, the production
of neurotoxic catecholamine o-semiquinones, and the loss of trophic
factors. These lesions may result in disorders in related mechanisms
such as cell-adhesion factors, membrane lipids, receptors, etc..
The following risk factors are suggested (numbers (i)-(iii) have
been reported to be present in schizophrenia): -

(i) Reduced antioxidant defenses leading to increased
ROS attack on synaptic structures and increased oxidation of catecholamines
to form neurotoxic o-quinones.

(ii) Impaired function of COMT leading to increased
levels of neurotoxic catecholamine o-semiquinones.

(iii) Defects in the synthesis of neuromelanin.

(iv) Impaired function of the enzyme DT-diaphorase
(Segura-Aguilar, personal communication), which converts aminochromes
to the nontoxic o-hydroquinones and so inhibits the formation
of the o-semiquinone..

(i) the status of neuromelanin in the catecholaminergic
neurons in the SN, LC and C1-C3 groups of neurons in the brain
in schizophrenia.

(ii) Determining in normal brains if the pigmented
neurons of the C1 and C3 groups in the medulla are adrenergic
or noradrenergic.

(iii) the details of where catecholamine o-quinones
are synthesized in the brain and further details of the pathways
involved.

(iv) a search for further metabolites on the neuromelanin
pathway, particularly 5,6-dihydroxyindoles and their O-methylated
metabolites, as well as 5-cysteinyl and 5-glutathionyl derivatives,
in the brain and body fluids and their status in schizophrenia.
If the C1 & C3 adrenergic neurons in the medulla do not produce
neuromelanin, it would be worth while to see if they do or do
not contain 5-cysteinyl adrenaline, or adrenolutin derived from
adrenaline and any 0-methylated o-quinone metabolites.

(v) further studies on the enzymology, pharmacology,
psychopharmacology, and physiology of catecholamine o-quinones
and their metabolites.

(vi) further studies of redox mechanisms at the glutamate
synapse and their possible role in normal and abnormal synaptic
plasticity.

(vii) further exploration of the role of the adrenergic
projection to the medial thalamus and its possible relationship
to the action of neuroleptics at this site (Cohen and Wan, 1995).

(viii) further studies of the mechanism of the antioxidant
properties of catecholamines.

It is further suggested that any clinical studies
should be carried out according to the guide lines laid out by
Stevens (1997).